We determined that HIV- 1 gp120 binds to an activated form of alpha4beta7, the gut homing receptor. Because alpha4beta7 is the principal integrin involved in lymphocyte homing to the lamina propria of gut associated lymphoid tissue (GALT), and HIV-infected CD4 T-cells preferentially localize to lymphoid tissues, particularly GALT, our finding suggests that a direct interaction between HIV gp120 and alpha4beta7 may be necessary for preferential establishment and/or maintenance of HIV replication in GALT. gp120-binding to alpha4beta7 is mediated by an LDV peptide sequence in the V2 loop that reiterates a structurally homologous binding motif present on MadCAM-1, VCAM-1 and fibronectin, the natural ligands for alpha4beta7. Removal of this sequence in the HIV envelope abrogates binding to alpha4beta7 integrin. A prototypical alpha4beta7 peptide antagonist based on the LDV sequence abrogates binding to gp120. Thus, HIV has acquired, through molecular mimicry, a mechanism to bind to the integrin receptor principally involved in directing lymphocytes to the lamina propria of the gut, the primary site of HIV replication. Viruses including HIV-1 spread from cell to cell via structures termed virological synapses that mimic immunological synapses. On CD4+ T cells, gp120 engagement of apha4beta7 results in a rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses. Activation of LFA-1 is known to increase HIV replication. Moreover, this interaction leads to a direct association of FAK within the cytoplasmic domain of CD4. This novel observation, when coupled with our previous demonstration that gp120 mediates Lck mobilization, chemokine receptor mediated Ca2+ flux and phosphorylation of FAK, suggests that gp120 signaling through alpha4beta7, CD4 and CCR5 induces the formation of a virological synapse to promote HIV infection. It is interesting that these HIV-specific signaling events functionally overlap T cell signaling involved in the formation of immunological synapses. By characterizing the signaling events mediated by gp120 we hope to better understand their role in viral replication and AIDS associated immunopathogenesis.